July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
HTRA1 inactivates Thrombospondin-1 mediated subretinal immune-suppression
Author Affiliations & Notes
  • Florian Sennlaub
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Fanny Beguier
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Michael Housset
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Sebastien Augustin
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Christophe Roubeix
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Thibaud Mathis
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Chiara M Eandi
    Hôpital XV/XX, France
  • Sara Touhami
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Jean-Baptiste Conart
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Yvrick Zagar
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Mustapha Benchaboune
    Hôpital XV/XX, France
  • Jean-François Girmens
    Hôpital XV/XX, France
  • Thierry D Leveillard
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Jose Alain Sahel
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Przemyslaw Mike Sapieha
    Université de Montréal, Quebec, Canada
  • Xavier Guilonneau
    Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
  • Footnotes
    Commercial Relationships   Florian Sennlaub, None; Fanny Beguier, None; Michael Housset, None; Sebastien Augustin, None; Christophe Roubeix, None; Thibaud Mathis, None; Chiara Eandi, None; Sara Touhami, None; Jean-Baptiste Conart, None; Yvrick Zagar, None; Mustapha Benchaboune, None; Jean-François Girmens, None; Thierry Leveillard, None; Jose Sahel, None; Przemyslaw Mike Sapieha, None; Xavier Guilonneau, None
  • Footnotes
    Support  This work was supported by grants from INSERM, ANR Geno 2009 (R09099DS), ANR MACLEAR (ANR-15-CE14-0015-01), LABEX LIFESENSES [ANR-10-LABX-65] supported by the ANR (Investissements d'Avenir programme [ANR-11-IDEX-0004-02]), Carnot, and the Association de Prévoyance Santé de ALLIANZ, and a generous donation by Doris and Michael Bunte.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1723. doi:
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    • Get Citation

      Florian Sennlaub, Fanny Beguier, Michael Housset, Sebastien Augustin, Christophe Roubeix, Thibaud Mathis, Chiara M Eandi, Sara Touhami, Jean-Baptiste Conart, Yvrick Zagar, Mustapha Benchaboune, Jean-François Girmens, Thierry D Leveillard, Jose Alain Sahel, Przemyslaw Mike Sapieha, Xavier Guilonneau; HTRA1 inactivates Thrombospondin-1 mediated subretinal immune-suppression. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1723.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The molecular mechanism responsible for the linkage of the major Age-related Macular Degeneration (AMD)-risk haplotype of the 10q26 locus is poorly understood. We previously showed that the breakdown of the physiological immune-suppression and an accumulation of pathogenic macrophages (Mphis) in AMD is due in part by the lack of CD47 activation by the C-terminal domain of Thrombospondin 1 (TSP-1). We here investigated the influence of the 10q26 locus on PLEKHA1, ARMS2 and HTRA1 expression in human monocytes and evaluated the effect of HTRA1 on TSP-1 CD47 signaling.

Methods : PLEKHA1, ARMS2 and HTRA1 expression was analyzed in human monocytes (Mo) from 18 homozygous 10q26 AMD-risk carriers and 18 homozygous non-carriers by RT-PCR and Elisa. The effect of HTRA1 on recombinant TSP1 and its C-terminal domaine was analyzed on electrophoreses gels, WB, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The biological effect of HTRA1-induced TSP1 hydrolysis was evaluated in Mo/retinal pigment epithelial (RPE) co-cultures, subretinal monocyte injections and light-induced subretinal Mphi-accumulation in vivo.

Results : We here show that circulating Mo from homozygous carriers of the major AMD-risk haplotype of the 10q26 locus significantly overexpress HTRA1, but not ARMS2 or PLEKHA1. Mphis in AMD donor eyes strongly express the High-Temperature Requirement A Serine Peptidase 1 (HTRA1) independently of the risk-haplotype. Mechanistically, we demonstrate that HTRA1 hydrolyses TSP-1 separating its two CD47-binding VVM sites necessary for efficient CD47 activation. We show that HTRA1-induced exaggerated Mo survival in RPE co-cultures in vitroand subretinal MPs accumulation in vivo, is dependent on TSP-1 deactivation. This pathogenic effect of HTRA1 was reversible by synthetic CD47 agonists.

Conclusions : Our study reveals that HTRA1 is strongly expressed in Mphis in AMD donor and over-expressed in 10q26 AMD-risk carriers. We show that HTRA1-mediated hydrolyses the C-terminal domain of TSP-1 inhibits its immune-suppressive activity, thereby leading to the exaggerated survival and accumulation of pathogenic Mphi. Our work uncovers a comprehensive mechanism how HTRA1 participates in the pathogenesis of AMD and opens new therapeutic avenues to restore subretinal immunosuppressivity and inhibit the pathogenic subretinal inflammation.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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